Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing
so they stop growing or die. Combining more than one drug may kill more tumor cells.
Peripheral stem celltransplantation may allow the doctor to give higher doses of
chemotherapy drugs and kill more tumor cells.

PURPOSE: Phase II trial to study the effectiveness of combination chemotherapy followed by
peripheral stem cell transplantation in treating children who have newly diagnosed
neuroblastoma.

Description

OBJECTIVES:

- Determine the toxicity and feasibility of high-dose thiotepa and cyclophosphamide with
autologous peripheral blood stem cell (PBSC) transplantation and sargramostim (GM-CSF)
followed by high-dose carboplatin, etoposide, and melphalan with second PBSC
transplantation, GM-CSF, and isotretinoin after induction in children with newly
diagnosed high-risk neuroblastoma.

- Determine the role of the meta-iodobenzylguanidine (MIBG) scan in assessing response to
tandem transplantation and minimal residual disease therapy in these patients.

- Determine the feasibility of quantitative polymerase chain reaction for
neuroblastoma-specific ribonucleic acids at specific stages of treatment as a
prognostic indicator of outcome in these patients.

- Determine the immune recovery by quantitation of lymphocyte subsets in these patients
and limited functional analysis after completion of this regimen.

- Course 2: Patients receive vincristine IV and doxorubicin IV over 15 minutes on
day 1, cyclophosphamide IV over 6 hours on days 1 and 2, and sargramostim (GM-CSF)
SC beginning on day 3 and continuing until PBSC are harvested. Beginning after
completion of course 2 and when blood counts recover, autologous PBSC are
harvested.

- Course 3: Patients receive VP-16 IV over 1 hour and ifosfamide IV over 1 hour on
days 1-5 and G-CSF SC beginning on day 6 and continuing until blood counts
recover.

- Course 4: Patients receive VP-16 IV over 1 hour on days 1-3, carboplatin IV over 2
hours (beginning after VP-16 infusion) on days 1 and 2, and G-CSF SC beginning on
day 4 and continuing until blood counts recover.

- Course 5: Patients receive treatment as in course 2 but supported by G-CSF.
Courses 1-5 each last 3-4 weeks. Patients undergo resection of the primary tumor
after course 4 or 5 unless primary resection was completed at diagnosis (which is
not recommended), no primary site is found, or the primary site is unresectable.
Patients complete courses 1-5 and then proceed to the first conditioning/PBSC
transplantation (PBSCT) in the absence of disease progression or unacceptable
toxicity.

- First conditioning/PBSCT: Patients receive high-dose thiotepa IV on days -7 to -5 and
cyclophosphamide IV over 1 hour on days -5 to -2. CD34+ PBSC are reinfused on day 0.
GM-CSF is administered SC beginning on day 5 and continuing until blood counts recover.
If blood counts have not recovered by day 28, unselected PBSC are reinfused. In the
absence of disease progression or unacceptable toxicity, patients proceed to the second
conditioning/PBSCT.

- Second conditioning/PBSCT: Beginning within 6-8 weeks after initiating the first
conditioning, patients receive high-dose carboplatin IV continuously and etoposide
phosphate IV continuously on days -7 to -4 and melphalan IV on days -7 to -5. PBSC and
GM-CSF are administered as in the first PBSCT.

Beginning no earlier than day 28 after the second PBSCT, patients undergo local radiotherapy
to the primary site and sites that are positive by meta-iodobenzylguanidine scan after
induction twice a day for 7 days (or once a day for 12 days if twice daily dosing is not
possible). Beginning on day 90 after the second PBSCT, patients receive oral isotretinoin
twice a day for 2 weeks. Treatment repeats every 4 weeks for 6 courses in the absence of
disease progression or unacceptable toxicity.

Patients are followed every 3 months for 1 year, every 6 months for 1 year, and then
annually thereafter.

PROJECTED ACCRUAL: A total of 31-39 patients will be accrued for this study within 22
months.

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Medical and Biotech [MESH] Definitions

Etoposide

A semisynthetic derivative of PODOPHYLLOTOXIN that exhibits antitumor activity. Etoposide inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces breaks in double stranded DNA and prevents repair by topoisomerase II binding. Accumulated breaks in DNA prevent entry into the mitotic phase of cell division, and lead to cell death. Etoposide acts primarily in the G2 and S phases of the cell cycle.

Cisplatin

An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle.

Cyclophosphamide

Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the LIVER to form the active aldophosphamide. It has been used in the treatment of LYMPHOMA and LEUKEMIA. Its side effect, ALOPECIA, has been used for defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer.

Carboplatin

An organoplatinum compound that possesses antineoplastic activity.

Doxorubicin

Antineoplastic antibiotic obtained from Streptomyces peucetius. It is a hydroxy derivative of DAUNORUBICIN.

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